This invention relates to peptide derivatives which are useful as therapeutic agents in the treatment of gastroenterological disorders.
Peptide YY (PYY) is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc. Natl. Acad. Sci. 79:2514, 1982). Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the amino acid tyrosine in the peptide nomenclature). In addition PYY shares a number of central and peripheral regulatory roles with its homologous peptide neuropeptide Y (NPY), which was originally isolated from porcine brain (Tatemoto, Proc. Natl. Acad. Sci. 79:5485, 1982). In contrast with the cellular location of PYY, NPY is present in submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol. Metab. 1:168, 1990), and they are also thought to attenuate basal (Cox et al. Br. J. Pharmacol. 101:247, 1990; Cox et al. J. Physiol. 398:65, 1988; Cox et al. Peptides 12:323, 1991; Friel et al. Br. J. Pharmacol. 88:425, 1986) and secretagogue-induced intestinal secretion in rats (Lundberg et al. Proc. Natl. Acad. Sci USA 79:4471, 1982; Playford et al. Lancet 335:1555, 1990) and humans (Playford et al. supra), as well as stimulate net absorption (MacFadyen et al. Neuropeptides 7:219, 1986). Furthermore, plasma PYY levels have been reported to be elevated in several diseases that cause diarrhea (Adrian et al. Gastroenterology 89:1070, 1985). Taken together, these observations suggest that PYY and NPY are released into the circulation after a meal (Adrian et al. Gastroenterology 89:1070, 1985; Balasubramaniam et al. Neuropeptides 14:209, 1989), and thus may play a physiological role in regulating intestinal secretion and absorption, serving as natural inhibitors of diarrhea.
A high affinity PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol. Metab. supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J. Physiol. supra), while C-terminal fragments of NPY were found to be less effective in their antisecretory potency than PYY (Cox et al. Br. J. Pharmacol. supra). Structure-activity studies using several partial sequences have led to the identification of PYY(22-36) as the active site for interacting with intestinal PYY receptors (Balsubramaniam et al. Pept. Res. 1:32, 1988).
In addition, PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week 506:623, 1993), cell proliferation (see, e.g., Laburthe, Trends Endocrinol. Metab. 1:168, 1990; Voisin et al. J. Biol. Chem, 1993), lipolysis (see, e.g., Valet et al., J. Clin. Invest. 291, 1990), and vasoconstriction (see, e.g., Lundberg et al., Proc. Natl. Acad. SCi., USA 79: 4471, 1982).
The amino acid sequences of porcine and human PYY are as follows:
porcine PYY YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY (SEQ. ID. NO. 1) PA0 human PYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ. ID. NO. 2) PA0 Asp=D=Aspartic Acid PA0 Ala=A=Alanine PA0 Arg=R=Arginine PA0 Asn=N=Asparagine PA0 Cys=C=Cysteine PA0 Gly=G=Glycine PA0 Glu=E=Glutamic Acid PA0 Gln=Q=Glutamine PA0 His=H=Histidine PA0 Ile=I=Isoleucine PA0 Leu=L=Leucine PA0 Lys=K=Lysine PA0 Met=M=Methionine PA0 Phe=F=Phenylalanine PA0 Pro=P=Proline PA0 Ser=S=Serine PA0 Thr=T=Threonine PA0 Trp=W=Tryptophan PA0 Tyr=Y=Tyrosine PA0 Val=V=Valine PA0 Orn=Ornithine PA0 Nal=2-napthylalanine PA0 Nva=Norvaline PA0 Nle=Norleucine PA0 Thi=2-thienylalanine PA0 Pcp=4-chlorophenylalanine PA0 Bth=3-benzothienyalanine PA0 Bip=4,4'-biphenylalanine PA0 Tic=tetrahydroisoquinoline-3-carboxylic acid PA0 Aib=aminoisobutyric acid PA0 Anb=.alpha.-aminonormalbutyric acid PA0 Dip=2,2-diphenylalanine PA0 Thz=4-Thiazolylalanine
The amino acid sequence for dog PYY and rat is the same as porcine PYY.